Pyridoxamine (chemical name 4-aminomethyl-3-hydroxy-5-hydroxymethyl-2-methylpyridine; alternate names 4-(aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol, and 4-(aminomethyl)-5-hydroxy-6-methyl-3-pyridinemethanol) is a promising pharmaceutical agent for the prevention of diabetic complications that is currently in clinical trials (as the dihydrochloride salt, trade name PYRIDORIN™). Drug development and commercialization requires the large scale manufacture (e.g., on the 100 kg scale or larger) of the active pharmaceutical ingredient (API). Commercially viable processes for the large scale manufacture of an API must provide good yields of a very pure product while still being very economical.
Two general routes for the chemical synthesis of pyridoxamine (I) are known where the starting material is the readily and economically available pyridoxine (II) (vitamin B6). One route uses oxidative methods, while the other uses non-oxidative methods.
Pyridoxine is the stable alcohol form of the B6 vitamers, which is converted metabolically to the coenzymatically active B6 forms. The first step in the metabolism of pyridoxine is an enzymatic oxidation of the alcohol group to an aldehyde, thus converting pyridoxine (II) to pyridoxal. The oxidative chemical synthetic parallels this by utilizing oxidizing agents such as manganese dioxide to convert pyridoxine (II) to pyridoxal. However, the oxidation of pyridoxine is problematic at the scale required for commercial manufacturing for several reasons, including the need to rapidly remove large amounts of solid oxidants to minimize the potential for continuing oxidation reactions. Such overoxidation not only can convert pyridoxal to pyridoxic acid but can also lead to non-selective oxidation of the second hydroxymethyl group at the 5-position. Other difficulties can be encountered subsequent to the formation of pyridoxal. For example, in order to form the desired amine, pyridoxal is conveniently reacted with hydroxylamine to form an intermediate oxime that must be subsequently reduced. Hydroxylamine is a dangerous reagent to handle on an industrial scale due to its instability, its high reactivity and its toxicity. Reduction of the oxime is known and can be performed by methods such as using zinc, as described for instance in JP-09221473. This is also an unfavorable reagent for large scale manufacturing. Reduction with hydrogen catalysts such as platinum or palladium is possible, but this route is expensive, difficult to control, and difficult to scale up. Over-reduction can lead to the generation of deoxy impurities that may be toxic anti-metabolites contaminating the API.
Clearly, non-oxidative methods are conceptually preferable to the oxidative methods. A direct, non-oxidative conversion of the pyridoxine alcohol to pyridoxamine would avoid the costs and difficulties associated with oxidative methods. However, non-oxidative methods appear to have been rarely reported in the literature. U.S. Pat. No. 2,522,407 describes a direct method of forming the amine by reacting ammonia in methanol solution with either pyridoxine or its esters. The disclosure exemplified the synthesis at the very small scale of 10 mg. Although this reaction scheme is conceptually interesting for its simplicity and low reagent cost, it requires an ammonia pressure reactor. Thus even if the yield can be made acceptable, this will remain a hindrance at the large (manufacturing) scale needed to produce API.
There are currently no or few processes described that are suitable for the large scale economical manufacturing required to produce pyridoxamine or salts thereof, for use as an API that is free of impurities at levels acceptable for FDA-approved drugs. Thus, there is a need in the art for economical, large-scale, and non-oxidative synthetic methods for the production of pyridoxamine or salts thereof.
The Gabriel synthesis is a process for forming primary alkyl amines from the corresponding alkyl halides. The general synthesis involves a nucleophilic attack by an imide anion, typically the phthalimide anion, (which can be generated in situ) at an alkyl halide. Displacement of the halide, or another leaving group in other instances, generates an N-alkyl imide by an SN2 substitution mechanism. In the case of phthalimide, the primary alkyl amine is released upon hydrolysis or hydrazinolysis of the N-alkyl phthalimide. The reaction with phthalimide can be applied to compounds with good leaving groups other than halides, such as esters. Furthermore, Gabriel reagents are not restricted to imides and a variety have been described (see for example Ragnarsson et al., Acc. Chem. Res., 24(10), 285 (1991)).